Cellular hypoxia is not only a common clinical problem which occurs, for example, as a result of acute and chronic pulmonary and cardiovascular conditions, but is also an important micro-environmental factor that influences normal embryonic development. Hepatocytes, like other mammalian cell types, are critically dependent on adequate oxygen tissue levels for development, survival and normal function. Hypoxia Inducible Factor-1 and -2 (HIF-1 and HIF-2) are heterodimeric basic-loop-helix transcription factors and are key mediators of cellular adaptation to diminished oxygen supply. Previously we have shown that increased expression of HIF in hepatocytes results in the development of cavernous hemangiomas, polycythemia and hepatocellular steatosis. We hypothesize that HIF-2 is the key regulator in the hypoxic induction of liver erythropoietin and angiogenic gene expression and plays a key role in liver lip genesis. We furthermore hypothesize that glycolytic gene expression in hepatocytes is mainly controlled by HIF-1. Studies are proposed that investigate the specific roles of HIF-1 and HIF-2 in the regulation of angiogenic and metabolic gene expression by use of transgenic and compound conditional knock-out mice that either lack or over- express HIF-1 or HIF-2 as a result of VHL gene deletion. We also propose studies that aim at the identification of novel HIF-2 specific targets using a combination of genome scale expression profiling and promoter microarrays. Our investigations will help to understand the unique roles of hypoxic signaling through HIF-1 and HIF-2 with regard to liver angiogenesis, hepatic glucose and fat metabolism, as well as the regulation of liver EPO. The data generated from this grant application will be used as basis for a five year NIH grant application that investigates HIF-dependent and HIF-independent hypoxic signaling in the context of liver disease. [unreadable] [unreadable] [unreadable]